Updates on juvenile idiopathic arthritis: Classification and treatment strategy

As the most common type of chronic arthritis in children, juvenile idiopathic arthritis (JIA) can lead to long-term disability and requires precise management based on the particular JIA category. At a recent industry-sponsored webinar, Dr Nicolino Ruperto, paediatrician at the IRCCS Istituto Giannina Gaslini and senior scientist of the Paediatric Rheumatology International Trials Organisation (PRINTO, www.printo.it), Genova, Italy, shared updates in classification and management of JIA, including the latest clinical evidence from the phase III clinical trial of secukinumab, an anti–interleukin (IL)-17A.

JIA: A heterogeneous disease
JIA is an umbrella term, which groups all forms of arthritis with unknown origin that begin before the age of 16 years and persist for more than 6 weeks. It is currently classified as per the 2004 International League of Associations for Rheumatology (ILAR) classification criteria. The ILAR criteria identify several mutually exclusive JIA disease categories: systemic arthritis, oligoarthritis, rheumatoid factor (RF)–negative polyarthritis, RF-positive polyarthritis, psoriatic arthritis (PsA), enthesitis-related arthritis (ERA) and undifferentiated arthritis. [J Rheumatol 2004;31:390-392]

It is increasingly recognized that JIA is, in fact, a heterogeneous group of diseases with manifesting joint inflammation, which vary in clinical phenotypes, outcomes, and pathophysiology. [Lancet Child Adolesc Health 2019;3:255-263; J Rheumatol 2019;46:190-197]

The new PRINTO classification
Recent advances have shown that while some JIA categories identify quite definite disease entities, others still include heterogeneous conditions. Some aspects of JIA classification and nomenclature therefore need to be reconsidered.

“A new classification is needed to distinguish between arthritis typical of children from arthritis that represents the childhood onset of diseases observed also in adults,” emphasized Ruperto. “This is very important for transition [of care] as well as for drug registration for paediatric patients.” [J Rheumatol 2019;46:190-197; Ann Rheum Dis 2012;71:1437-1439; Ann Rheum Dis 2010;69:1260-1263]

Using an evidence-based approach, PRINTO provided a preliminary proposal for revisions to the current classification criteria. JIA is provisionally defined by PRINTO as a group of inflammatory disorders (systemic JIA, RF-positive JIA, enthesitis/spondylitis-related JIA, early-onset antinuclear antibody–positive JIA, other JIA, unclassified JIA) that begin before the age of 18 years and persist for at least 6 weeks; other known conditions are excluded. [J Rheumatol 2019;46:190-197] This proposal is currently under validation with a large data collection of at least 1,000 new-onset JIA patients.

EPOCA: JIA epidemiology and global treatment patterns
In addition to its heterogeneity, there are unexplained disparities in the prevalence of JIA categories across geographic regions or racial/ethnic groups, as shown by several epidemiological studies, which make comparing different study cohorts difficult. [Lancet Child Adolesc Health 2019;3:255-263]

To better understand the clinical heterogeneity of JIA, the EPOCA (Epidemiology, Treatment, and Outcome of Childhood Arthritis) study was conducted in 9,081 children with JIA from 130 paediatric rheumatology centres in 49 countries between April 2011 and November 2016. In the study, researchers compared the epidemiology of the JIA categories, treatments used, availability of biologic agents, and treatment outcomes of paediatric patients in different geographical areas. [Lancet Child Adolesc Health 2019;3:255-263]

In Southeast Asia, systemic arthritis and RF-positive polyarthritis were found to be more common, while oligoarthritis and RF-negative polyarthritis were less common, compared with other regions. In addition, a higher prevalence of ERA was observed in Southeast Asia. The category of PsA was uncommon in all regions. [Lancet Child Adolesc Health 2019;3:255-263]

Compared with ERA, PsA patients were more likely to be female (65.4 percent vs 27.5 percent; p<0.001) and had a younger median age at disease onset (8.1 years vs 10.1 years; p<0.001), longer disease duration (3.9 years vs 3.4 years; p<0.001), and a higher rate of comorbidities (29.8 percent vs 15.7 percent; p<0.001). The most common comorbidity for PsA and ERA was psoriasis and inflammatory bowel disease, respectively. Both PsA (78.6 percent) and ERA (84.6 percent) patients were most commonly treated with NSAIDs. Biologics were used in 40.1 percent of PsA patients and 34.3 percent of ERA patients (p<0.001). [Lancet Child Adolesc Health 2019;3:255-263]

“Without a doubt, biologics play an important role in JIA treatment. EPOCA showed that two tumour necrosis factor [TNF] inhibitors, etanercept and adalimumab, were most widely used,” said Ruperto. [Lancet Child Adolesc Health 2019;3:255-263]

In terms of outcomes, sacroiliitis, dactylitis and enthesitis were reported in 9.5 percent, 5.3 percent and 27.8 percent of ERA patients, and in 5.5 percent, 14.4 percent and 9.9 percent of PsA patients, respectively. Morning stiffness lasting >15 minutes and pain were reported in 26.1 percent and 68.5 percent of ERA patients, and in 21.3 percent and 66.0 percent of PsA patients, respectively. Notably, 18.1 percent of ERA patients and 13.2 percent of PsA patients reported difficulty in remaining seated for a long time. [Lancet Child Adolesc Health 2019;3:255-263]

JIA treatment options and guidelines
“Since 2000, there has been an exponential increase in drug options, especially biologics, most of which have been approved for use in children,” Ruperto pointed out. [Nat Rev Rheumatol 2015;11:290-300]

The 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of JIA provided 39 recommendations on therapeutic approaches for non-systemic polyarthritis, sacroiliitis and enthesitis, including the use of NSAIDs, disease-modifying antirheumatic drugs (DMARDs), biologics, and intraarticular and oral glucocorticoids. However, most recommendations were supported by evidence of ‘low’ or ‘very low’ quality, meaning they were essentially based on expert opinion of the guideline’s coauthors. [Arthritis Rheumatol 2019;71: 846-863]

A simplified step-up treatment strategy was proposed in early 2022 to guide corresponding treatment steps for oligoarticular JIA (≤4 joints), polyarticular course JIA (≥5 joints) and systemic JIA (arthritis and fever), based on the severity of disease. Biologics are recommended as one of the cornerstones of treatment for polyarticular course JIA and systemic JIA. [Nat Rev Dis Primers 2022;8:5]

Phase III clinical trial of secukinumab in ERA and JPsA
Secukinumab, a fully human anti–IL-17 monoclonal antibody, is shown to be efficacious and safe in paediatric patients with ERA or juvenile PsA (JPsA) in a randomized, double-blind, placebo-controlled, treatment-withdrawal, phase III clinical trial conducted by researchers from PRINTO and the Paediatric Rheumatology Collaborative Study Group (PRCSG) networks. The trial included 86 biologic-naïve patients aged 2–17 years with JPsA or ERA. In treatment period (TP) 1, patients were given open-label subcutaneous secukinumab (75 mg in patients <50 kg, 150 mg in patients ≥50 kg; weekly up to week 4 and Q4W afterwards) until week 12. Patients who achieved at least JIA American College of Rheumatology (ACR) 30 response in TP1 progressed onto TP2 and were randomized 1:1, in a double-blind fashion, to either stay on secukinumab or switch to placebo until up to week 100. Patients with JIA disease flare in TP2 entered open-label secukinumab TP3 that will last up to week 104. [Ann Rheum Dis 2022;doi:10.1136/ard-2022-222849]

The study’s primary endpoint was met, showing a significantly longer time to disease flare in TP2 with secukinumab vs placebo (flare events: 27 percent vs 55 percent; hazard ratio, 0.28; 95 percent confidence interval [CI], 0.13–0.63; p<0.001). (Figure 1)

The estimated median time to disease flare was 453 days in the placebo group, and not calculable in the secukinumab group since <50 percent of patients on secukinumab had flared at the time of study completion, indicating prolonged efficacy of secukinumab.

Significant improvement in ACR responses from baseline
At week 12, 87.2 percent, 83.7 percent, 67.4 percent, 38.4 percent, and 24.4 percent of secukinumab-treated patients achieved JIA ACR 30, JIA ACR 50, JIA ACR 70, JIA ACR 90, and JIA ACR 100 response, respectively. (Figure 2) [Ann Rheum Dis 2022;doi:10.1136/ard-2022-222849]

“Nearly 70 percent of the population achieved ACR 70 response,” said Ruperto. “Interestingly, more than one-third of secukinumab-treated patients achieved a status of inactive disease, meaning no disease was detected after 3 months of treatment.”(Figure 2)

“Secondary analysis demonstrated superiority of secukinumab vs placebo in prolonging time to disease flare, regardless of methotrexate use at baseline,” said Ruperto.

During the study, there were no cases of mycobacterial infections, hepatitis B reactivation, malignancy or deaths, and no anti-secukinumab antibodies were detected. In patients with ERA or JPsA, secukinumab was generally well tolerated, with a safety profile consistent with that previously observed in adult patients with axial spondyloarthritis and PsA.

Secukinumab is approved by the US FDA and EMA for treatment of JPsA and ERA. [Medicine (Kaunas) 2022;58:1552]

Summary
New recommendations for JIA classification and treatment strategies are expected to help clinicians develop more comprehensive disease management plans. Latest data from a randomized controlled clinical trial support the efficacious and safe use of secukinumab in paediatric patients with ERA or JPsA.